As for many forms of experience-dependent plasticity, modifications in glutamatergic synaptic transmission have been suggested to be particularly important. However, evidence of such changes in response to in vivo administration of drugs of abuse is lacking. This article demonstrates that a single in vivo exposure to cocaine induces long-term potentiation of AMPA-receptor-mediated currents at excitatory synapses onto dopamine cells in the ventral tegmental area. Potentiation is still observed 5 but not 10 days after cocaine exposure and is blocked when an NMDA receptor antagonist is administered with cocaine. Furthermore, long-term potentiation at these synapses is occluded and long-term depression is enhanced by in vivo cocaine exposure. These results show that a prominent form of synaptic plasticity can be elicited by a single in vivo exposure to cocaine and therefore may be involved in the early stages of the development of drug addiction. The cellular mechanisms thought to be involved in adaptive forms of experience-dependent plasticity may be maladaptively usurped by drugs of abuse. Figures, notes